The c-Met gene encodes a heterodimeric transmembrane receptor (Hepatocyte Growth Factor Receptor, HGFR) with intrinsic tyrosine kinase activity and is composed of an alpha chain disulphide-linked to a beta chain. The beta chain (subunit) binds a c-Met ligand, hepatocyte growth factor (HGF). The alpha chain (subunit) contains an intracellular tyrosine kinase domain that mediates activation of a number of intracellular signal transduction pathways (cascades).
Intracellular signaling through c-Met is associated with regeneration of liver and kidney, embryogenesis, hematopoiesis, muscle development, and in the regulation of migration and adhesion of normally activated B cells and monocytes. The c-Met gene is primarily expressed in epithelial cells and has been found to be overexpressed or otherwise activated in a significant percentage of human cancers. Activation of c-Met may occur as a consequence of MET-gene activating mutations, MET-gene amplification/overexpression, and/or the acquisition of an HGF/c-Met autocrine loop. Any such development and/or combination can lead to cell scattering, angiogenesis, proliferation, enhanced cell motility, invasion, and/or the acquisition of metastatic properties to malignant cells. The overexpression of c-Met has, for example, been detected at the transition between primary tumors and metastasis. Using an Adenovirus-mediated RNA interference technique, inhibition of MET expression in hepatocellular carcinoma (HCC) cells was demonstrated in cell culture and animal model systems (Zhang et al., Mol Cancer Ther, 4:1577-1584, 2005).
Double-stranded RNA (dsRNA) agents possessing strand lengths of 25 to 35 nucleotides have been described as effective inhibitors of target gene expression in mammalian cells (Rossi et al., U.S. Patent Application Nos. 2005/0244858 and US 2005/0277610). dsRNA agents of such length are believed to be processed by the Dicer enzyme of the RNA interference (RNAi) pathway, leading such agents to be termed “Dicer substrate siRNA” (“DsiRNA”) agents. Additional modified structures of DsiRNA agents were previously described (Rossi et al., U.S. Patent Application No. 2007/0265220).